Rational design and synthesis of new acetamide–indole–benzo[d]imidazole–carboxylic acid hybrids as dual PTP1B/α-glucosidase inhibitors

Abstract

A series of novel acetamide–indole–benzo[d]imidazole–carboxylic acid hybrids (8a–n) was designed based on the structural scaffolds of known protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibitors. Evaluation against PTP1B revealed that six compounds (8d, 8f–h, 8j, and 8l) exhibited superior inhibitory activity compared to the standard inhibitor suramin, while one derivative (8a) demonstrated comparable potency. The remaining compounds showed reduced efficacy relative to suramin. In contrast, only two compounds (8j and 8k) displayed marginally superior α-glucosidase inhibition compared to acarbose, while all other derivatives were less potent than the standard. Based on these results, subsequent investigations focused on the PTP1B inhibitory potential of this series. Kinetic analysis of the most potent compound, 8l, confirmed a competitive inhibition mechanism against PTP1B. Molecular docking studies of the most active compounds yielded binding modes consistent with the in vitro activity, and molecular dynamics simulations further verified the stable binding of compound 8l within the PTP1B active site, supporting its potential as a lead PTP1B inhibitor.